Investigation into the regulatory mechanisms of resistance-nodulation-division efflux pumps in Acinetobacter spp.
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Date
2021-06-01
Authors
KAINTH, TAJINDER
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Abstract
Acinetobacter spp. play a significant role in colonizing and infecting immunocompromised patients in hospitals. They have been implicated in nosocomial infections in intensive care unit (ICU) patients. These infections are extremely hard to treat because of the broad resistance of these bacteria to numerous antimicrobials. A major contributor to Acinetobacter’s capability to cause these infections is its ability to sense and adapt to environmental and host stress signals, allowing it to persist in medical settings and human hosts. Intrinsic resistance can be generated by the interplay of decreased susceptibility due to active efflux systems and external stressors that bacteria experience. Catalase-peroxidases are enzymes responsible for detoxification of H2O2. The aim of this study is to study the regulatory mechanisms that control the expression of Resistance-Nodulation-Division (RND) efflux pumps in Acinetobacter spp. The first section of this thesis characterizes the involvement of catalase-peroxidases, katG and katE, in the oxidative stress -mediated antimicrobial susceptibility of Acinetobacter baumannii and second section characterizes a novel regulator of AdeDE RND efflux pump in Acinetobacter pittii. Mutants of A. baumannii ATCC17978 with deletions in katG and katE were tested for sensitivity to H2O2, RND efflux pump expression and susceptibility to antibiotics. katG and katE deletion resulted in reduced susceptibility to aminoglycoside antibiotics. Deletion of katG or katE results in adeB, gene that encodes the inner membrane component of AdeAB, an aminoglycoside pump and adeR, a response regulator that encodes the transcriptional activator of adeAB to be upregulated. RNA-Seq analysis was carried out to understand the global response of A. baumannii to oxidative stress revealed over 100 differentially expressed genes. Finally, a novel Tet-R type novel regulator upstream of AdeDE RND efflux pump in A. pittii was characterized. Deletion of the regulator results in overexpression of AdeDE efflux pump, reduced antibiotic susceptibility to multiple antibiotics, altered biofilm production and surface associated motility. These results indicate that efflux may be a part of A. baumannii’s response to oxidative stress, suggest that stress response are, thus, important determinants of antibiotic resistance in A. baumannii and AdeQ plays a role as a regulator of AdeDE RND efflux pump in A. pittii.
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Microbiology